Inflammation is caused by the emigration of inflammatory cells such as neutrophils, T-lymphocytes and eosinophils into the tissues, where they are activated. The inflammatory cells are likely to live longer at the site of inflammation due to growth factors and inflammatory mediators produced by the various cells. For instance in bronchial asthma a massive eosinophilia is present. Eosinophils contain cytotoxic granules in their cytoplasm and eosinophil activation/degranulation (lysis) seems to result in epithelial cell damage and airway hyperresponsiveness. Eosinophil survival is prolonged by growth factors such as IL5 and GM-CSF, which inhibit eosinophil apoptosis. Apoptosis is a physiological process of programmed cell death distinct from pathological necrosis. In apoptosis the granule contents of eosinophils are removed without harmfull effects characteristic of necrosis (i.e. inflammation and tissue damage).
Apoptosis is chararterised by specific biochemical and morphological changes including cell shrinkage, which may involve K+ efflux, surface blebbing, chromatin condensation and endonuclease-catalyzed DNA fragmentation. Mitochondria are likely to have an important role in regulating apoptotic mechanisms. The evidence is based on the fact that mitochondria contain various proteins that can activate the apoptotic process e.g caspases, cytochrome c, apoptosis inducing factor (AIF). Currently it is believed that a decrease in mitochondrial membrane potential followed by cell shrinkage and generation of reactive oxygen species precede nuclear alterations detected in apoptotic cells.
Agents which are able to open mitochondrial KATP channels (mitochondrial ATP dependent potassium channels) have been shown to induce mitochondria swelling by lowering the mitochondrial membrane potential (Szewczyk, A. and Marban, E., Trends Pharmacol Sci (1999) 20:157-161). The reduced membrane potential leads to opening of the mitochondrial permeability transition pore leading to volume dysregulation, which may finally cause mitochondrial membrane rupture.
Compounds of general formula (I) 
where X is CH2 or S, have been described in applicant's European Patent No. 383449 B1. The compounds sensitize troponin-C in the heart muscle cells to calcium and are useful in the treatment of congestive heart failure.
The compound of formula (I), where X is CH2, is simendan or [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile. Its optically active enantiomers have been described in applicant's European Patent No. 565546 B1. It was shown that the cardiotonic effects were predominantly due to the (−)-enantiomer of compound (I), i.e. levosimendan.
The effect of simendan to reduce infarct size and arrhythmias has been disclosed in WO 93/21921. It was also shown that the both enantiomers of simendan reduced arrhythmias, and that the (+) enantiomer increased survival. The use of levosimendan for the treatment of pulmonary hypertension has been disclosed in WO 99/66912.